TW200409756A - Novel compounds - Google Patents

Abstract

The present invention relates to novel pyridone derivatives capable of inhibiting α4 integrin mediated cell adhesion, processes for their preparation, compositions comprising them and their use in the treatment of diseases capable of being modulated by the inhibition of cell adhesion.

Description

200409756 发明, Description of the invention [Technical field to which the invention belongs] Cell adhesion is useful for the treatment of chronic inflammatory diseases. [Prior art] The present invention relates to a Xinlai compound, a step of preparing the compound, a composition containing the compound, and the use of the compound for treating diseases because it can regulate the inhibition of cells. More details ... The present invention relates to novel pyridone derivatives, which can inhibit the multiple adhesion interactions between white blood cells and endothelial cells or extracellular matrix proteins regulated by α4 integrin, which are important factors in the regulation of immunity and inflammation. . The earliest fact that leukocytes were removed from the inflammatory end of the vascular distribution includes the rolling of leukocytes followed by a change in integrin binding, causing subsequent strong adhesion (for a review see Butcher, 〇 // 67: 1〇33] 036 (1 991 ); Harlan, Mind "3.5 13-525 (1 985); Hemler? Annu. Rev. Immunol. 8: 365-400 (1990); Osborm, Cell 62: 3-6 (1 990); Shimizu et al. 5

Immunol Rev. 1 14: 1 09- 143 (1 990); Springer, Nature 346: 425-434 (1 990); and Springer, Cell 7 6:30 1 -3 1 4 (1994)). In response to chemokines, white blood cells move through two adjacent endothelial cells and enter partly by the extracellular matrix protein fibronectin (FN) (see Wayner et al "Ce // 5b /. 105: 1873-1884 (1987)) and Sheng Yuan (CN) (see Born stein et al. 5 mountain price odem, 49: 957- 1 003 (1 980); and Mil] e], Chemistry of the collagens and their distribution, in "Extracellular

Matrix Biochemistry ", K. A. Piez and A. H. Reddi, editor, 314938 200409756

Elsevier, Amsterdam, 41-78 (1 983)). The important identification molecules involved in the adhesion reaction belong to the integrin gene superfamily (for a review see Hemler, ^ Xian · / ㈣㈣ 如 / 8: 365-400 (1 990);

Hynes, Cell 48: 549-554 (1 987); Shimizu et al.? Immunol. 1 14.109-143 (1990); and Springer, TVaiwe 346: 425-434 (1990)).

Integrins are heterodimers composed of related non-covalently bonded subunits, which are also alpha and / 3 subunits. At present, 8 integrin units of 8 integrins have been identified, which can be combined with 16 different alpha subunits to form 23 different integrins. Known as VLA-4 (Very Late Antigen-4; integrin), the integrin continuously appears on the surface of white blood cells including lymphocytes, monocytes, eosinophils and white blood cells (see Hemler et al. , J. 5/0.

Ckm · 262: 1 1478-1 1485 (1 987); and Bochner et al ”J. Ind. M. 173.155:)-1556 (1991)). VLA-4 has been reported to be intoxicated in semitoxic patients Found on sexual white blood cells (see Ibbotson et al., Md 7: 465-470 (2001)). VLA-4 can bind to vascular cell adhesion molecules-l (vasculai · cell adhesion molec: iile_l; VCAM-1) 'leading to leukocyte leakage (Alices et al. 5 Ce // 6 0: 577-584 (1990)). Once the cells reach the extravascular space, they will bind to the connecting segment -l (connecting segment 1 CS-1), which is the alternate bonding region of the A-bond of FN (Wayne et al "J Ce // 仏. / 1 09..1 32 1-] 330 (1 989)). In addition, vla-4 is known to bind to produce osteoprotein, which is up-regulated in arteriosclerotic platelets

31493S 200409756 (see Bayless et al., J. 〇 // ι11: 1165-1 1 74 (1 998)). [Summary of the Invention] (Disclosure of the Invention) A novel series of compounds were discovered and they were found to inhibit cell adhesion regulated by the integrins. The present invention therefore provides, in the view of "2", the compound of formula (I) or a pharmaceutically acceptable derivative thereof:

(I) c02h where A and B are independently aryl or heteroaryl; Q is C, CH or together with the group 乂 or group 0 to form D is nitrogen, and C is an alkyl group or a group Q- R], R2 and R3 are independently betyl heterocycles; CK6 alkyl, halo, cyano, CF3 "shoky, c :. Where is lactyl, meridian, radical, betrayal Base, d 6-yl, amido, single di-c or di-C] -6 amines, or amines "", d amines, radicals (optionally up to three selected from C1. Identifiers, functins :: Etyl or cluttered groups (substituted for benzyl or cf3)) or chrysyl '^ CH2)]. 6NRxR > 3] 4938 7 200409756 where E is a single bond or -〇 CH2 •• and Rx and Ry are independently hydrogen, alkyl or combined to form a 5- to 7-membered heterocyclic ring; R4 is hydrogen, C ^ 6 alkyl, halogen or CV6 alkoxy; V is 0, S, NH, N-CV6 alkyl, NN〇2, NCN or together with the group Q to form a 5- to 7-membered heterocyclic ring; W, X, Y, Z are independently C, CH or CH2; ........ ................. means single or double bond; L is-(CH2) q- or-(CH2) q'〇- where q is 0,1,2 Or 3 and q, 2 or 3; J is (i) —CR5 = CR6 -Where R5 and R6 are independently hydrogen or alkyl; or (ii) -CHR7-CHR8-here R7 and R8 are independently hydrogen, C6 alkyl, C3-7 cycloalkyl, aryl, heteroaryl Group, -NHCOR9- or -NHS〇2R9- wherein R9 is as previously defined or-(CHJwNW where Rx and Ry are as previously defined; or (iii) a single bond; or (iv) -CHR6- where R6 is as previously defined; or (v) —〇-CHR] °-, -NRn-CHR] ()-or -CR] 2R] 3-CHR] ° -where R] G and Rn are independently hydrogen or (^ 6 alkyl and R ] 2 and R13 are independently a CV6 alkyl group or R12 and R13 are combined to form a C3_7 cycloalkyl group or a 5- to 7-membered heterocyclic ring; m, η, and p are independently 0, 1, 2, or 3; and t is 0, 1 or 2. A particularly preferred subclass of the compound of formula (I) is a compound of formula (I a)

31493S 200409756 or its pharmaceutically acceptable derivative:

Among them: R1 In this specification, unless specifically stated: The same name m is used to condense a group selected from the group consisting of gas, chlorine, mo, or group; Cambay's name $ 司 '' G, Sergeant, / 1 for soil In the description of the group or a part of the group and eight containing 1 to 6 Shilu ^ including methyl, B: an example of a straight or branched chain of f atom _ mono earth, propyl, isopropyl, n-butyl , Isobutyl, ditributyl, pentyl or hexyl; the name § Siken 55 di-phenyl and Zeeki (naphthalene-1 -yl and naphthalene-2-yl); the name 3 heteroaryl "sound%, It is Fang Yue Jie or Yi has 1 to 3 benzo aromatic rings selected from oxygen, nitrogen = heteroatoms. Suitable examples of these aromatic rings are 'fluorenyl' three. Sorry " m. Ambisoryl, diazolyl, isothiazolyl, isoxazolyl, thio :: soryl'pyridine. Sorry, ° density,... … Suitable examples of aromatic rings include quinolinyl, fluorenyl, 314938 200409756 D noise group, benzopyran I, benzothienylpyridyl, etc. 5 to 7-membered heterocyclic rings, meaning Refers to the mixture of 1 to 3 selected from nitrogen, oxygen and sulfur Non-aromatic heterocycles. Suitable examples of such rings include: hydropyridyl 'hexahydropuryl, pyrrolidinyl and morpholinyl, etc. The heterocyclic ring may be optionally substituted with c] -6 alkyl; the name j Cw alkane "Oxyl" is used to describe a group or a part of a group having a gas atom bonded to the aforementioned alkynyl group; examples of these include methoxy, ^ oxy, propoxy 'isopropoxy, Butoxy, isobutoxy, th ..., oxy and second-butoxy, pentyl or hexyloxy; the name 5 Division C] · 6 roasting group "is used for 4, known parties, Describe the groups generated by the C " carboxyl group of carboxylic acid 'and Η; examples of the poor temples include μmethyl, ethyl, and propyl butyl butyl; and the term "CS · 7 cycloalkyl "" Refers to a dialkyl group. Examples of these include% hexyl or cyclopentyl. ^ Definition of compound formula (I)

It should be understood that not only when 5 to 7 PR] substitutions are formed; ―-Q may be C but also in. When A and / or B is heterocyclic, when A and / or B is aryl, preferably benzylaryl is preferably pyridyl; suitably, A is phenyl or pyridyl; suitably, B is phenyl Pentyl 5 halo 'GCU 6 :! pentyl' amino 'suitably, R], R2 and R3 are independently alkoxy, hydroxyl, cyano, CF3, nitro, 314938 200409756 mono- or dioxane Amine, carboxyl, alkylamino, amido, mono- or mono-c " alkylamido, nhco r9 or nhs〇2R9 where r9 is alkyl, cs_7% alkyl or phenyl (up to as needed) Substituted with three groups selected from the group consisting of I · 6, halogen, alkoxy, cyano, phenyl, or cf3) or -E- (CH2)] _ 6NRxRy where E is a single bond or _〇CHd RX and Ry Independently hydrogen, C] · 6 alkyl or combined together to form a ring including hexahydropyridyl, hexahydropyridyl, pyrrolidinyl or morpholinyl, wherein the ring may optionally pass through C] _6 alkyl Substitution; when Q and V combine to form a ring including hexahydropyridyl, hexahydropyridyl, pyrrolidinyl or morpholinyl, it may optionally be substituted with Cw alkyl; when Q and D together Hexahydro In the case of a pyridyl, hexahydropyridyl, pyrrolidinyl or morpholinyl ring, it may optionally be substituted with an alkyl group; suitably, J is ⑴-CRLCR6 — where ... and M are independently hydrogen or C 1 6 alkyl groups; or (π) -CHR7-CHRL where f and R8 are independently hydrogen, alkyl, Cw cycloalkyl, phenyl, naphthyl, thienyl, furyl, pyrrolyl, triazolyl, Imidazolyl, oxazolyl, thiazolyl, oxadiazolyl, isothiazolyl, isoxazolyl, thiadiazolyl, pyrazolyl, pyrimidinyl, darazyl, pyrazolyl, pyridyl, quinolinyl , Isoquinolinyl, indolyl, benzofuranyl, benzothienyl, stilbenzyl, benzophosphingyl, -Nhcor9- or a nhs〇2r-where r.) Is as defined above or _ (CH2u) RXRy

3] 493S 200409756 where Rx and Ry are as defined above; or (iii) single bond; or (iv) -CHR6-here R6 is as defined above; or

(v) —0CHR] 0-,-NRn-CHR]. -Or-CR] 2R] 3CHR10-here R] G and Rn are independently hydrogen or (V6 alkyl and R12 and R13 are independently (: bu 6 alkyl or R12 and Ri3 together to form C3_ * 7 Sample-based, tetrazinopyranyl'hexaazapyridinyl, hexaazidinyl, pyrrolidinyl or morpholinyl; When m, η or ρ is not 0, preferred R], R2 And R3 individually include a CV6 alkyl group, a halogen, a Cu alkoxy group, a cyano group, or CF3. When m, η, or P is 2 or 3, R], R2, and R3 may be the same or different individually; preferably The ring contains W, X, Y and Z, wherein the ring nitrogen system is bonded to the L group;

Preferably, R], R2 and R3 are independently Cm alkyl, halogen or Cw alkoxy, when Q and V combine to form a 5- to 7-membered heterocyclic ring, a suitable example is where Q and V form benzene Part of a benzimidazole ring or a benzimidazole ring. When Q and D are combined to form a 5- to 7-membered heterocyclic ring, suitable examples are those in which Q and D form an indole ring; suitably, R4 is hydrogen or halogen; preferably, Q is CH or C (When substituted by R], V is 0 and D is hydrogen. 12 314938 200409756 Suitably, L is-(CH2) q- where q is 0, 1, 2 or 3. Preferably, L is -CH:-. Preferably, J is (i)-CR5 = CR6- where R5 and R6 are independently hydrogen or C] _6, or (ii) -CHR7-CHR8- where R7 and R8 are independently hydrogen, C ] 6 alkyl, C3_7 cycloalkyl, phenyl, _NHCOOR9-where R9 is C] alkyl; or (iii) a single bond; (iv) —CHR6- where R6 is as defined above; or (v) —〇-CHR] 0-,-NRn-CHR10- or -CR] 2R] 3CHR] 〇 Here R] G and Rn are independently hydrogen or C] -6 alkyl and p,] 2 and p,] 3 Independently C] · 6 :): End group or R] 2 and combined together to form C 3-7 jade sinter group; Chediji j is -⑶ 二 ⑶ ...- (CH2) 2-, -CHR7 -CH2- where R7 is alkyl. Suitably, R], Chi 2 and R 3 are independently C]. 6 alkyl, functional element, c 6 k group 'Singmei, Shu Qi mono-gongkong pore group, CF3, nitro, c] -6 alkane Thio, amine, di: alkylamino, carboxyl, alkylamido, amido, mono 1 ^ "alkylamido, NHCOR9 or NHs 02R9 where 9 is c] ^ cycloalkyl group or as needed A phenyl group substituted with at least three groups selected from the group C] 6 ^^ 6 & R ' I ' yl, or%: G C is not 0 '. Preferred R1 includes halogen ( In particular, fluorine or trifluoromethyl (especially methyl, when m is 2 or 3, R) may be the same as or different from 314938 13 200409756. Tian,. Gongdi m is 1 and R] is associated with The urea moiety has a halo group. When the field η is not 0, the preferred R2 includes halogen (especially fluorine or chlorine), ^ ^ \ (especially methyl) or C] · 6 alkane. Oxy group (especially methoxy group): when it is 2 or 3, R] may be the same or different. Most preferably n is 0 or n ^ 14 is an ortho-linked oxy group in which the associated urea moiety has an ortho relationship When p is not 0, the preferred R3 includes halogen (especially fluorine or chlorine) 3 C] 4 alkyl (especially Methyl). When P is 2 or 3, R3 may be the same or different. R4 is preferably hydrogen. Suitably, L is-(CHJq-where q is 0, 1, 2 or 3; suitably , J is (i) —CR5 = CR6- where M and R6 are independently hydrogen or Ci 6 alkyl; or (ii) -CHR7-CHRL here ... and R8 are independently hydrogen, C " alkyl'- NHCOR9- or _NHS〇2R9_ wherein R9 is as defined above; preferably fine 7-j: is C ^ 6 alkyl. Particularly preferred compounds of the present invention include Examples to E5ι (see later) or its medicine Acceptable derivatives. Particularly preferred compounds of the present invention include Examples E5, E9, E32, E41, E42 i ρς,, / t!) 1 or pharmaceutically acceptable derivatives. ”It should be understood that Compounds have one or more asymmetric carbon atoms as a result of 3] 4938 14 200409756 This can occur as racemates, racemic mixtures and individual mirror or isomers. All such isomeric forms include mixtures thereof Are included in the present invention. • U " Plant. 丨 Yitu, Αππ, b 1 he, cis (z) and trans (E) isoforms. The present invention includes the present invention hair Individual stereoisomers of the compounds and where appropriate, including their individual tautomeric forms' together with their mixtures. Non-mirromeric or cis and trans isomers can be separated by conventional techniques, such as Fractional crystallization, chromatography or hplc (high pressure liquid chromatography). A single stereoisomeric form of a medicament can be suitably prepared from the corresponding optically pure intermediate or by isolation, such as the muscle of the corresponding racemate using a suitable palm support, c = rotate and appropriate optical activity Acid or test reaction shape = staged crystallization of isomeric salts. Or a mixture of mirror isomers.1 Suitable palmitic compounds form a chemical counter library of new covalently bonded species: such as elimination of acid and palmitic amines or coupling to obtain non-mirror II; :: Do not (in this case individually The ground is-amine and cool), which can be isolated by conventional analysis, HPLC or segmented crystallization. The single ion = structure and then can be converted to the desired bond of the desired compound by, for example, 轫 1 ″ The appropriate chemistry of hydrolytic cleavage is a mirror image isomer early. 士 ϋ 用 方 f 木 立 Φ ^ 不 中, noun, pharmaceutically acceptable derivative drug acceptable salt, solvent into Cong Erji-Be Xinjiu Any doctor is administering to the recipient: the heart, such as the vinegar of the compound of the present invention, in order to provide (directly or indirectly) the compound 'or its active generation) before it is turned into a project or residue. Other derivatives can be familiar to the 15 200409756

/, 5th edition, Vol l: Principles which teaches the scope of 7F shai temple derivatives identified by the skilled person without experimentation. ,,-

The references shown in Chemistry and Drug Discovery, Section and Practice, are hereby incorporated by reference. Preferred pharmaceutically acceptable derivatives are salts, solvates, esters, carbamates and phosphates. Particularly preferred pharmaceutically acceptable derivatives are salts, solvates and esters. The most preferred pharmaceutically acceptable derivatives are salts and esters. Those skilled in organic chemistry should be aware that many organic compounds can form complexes with solvents. Here, these organic compounds are reacted with solvents or precipitated or crystallized. These complexes are known as solvates, 5. For example, complexes with water are known as "hydrates." Solvates of the compounds of the present invention are included in the scope of the present invention. As used herein, the term "prodrug" means that the compound can function in the body. The compounds are converted into pharmacologically active forms by, for example, hydrolysis in the blood. Pharmaceutically acceptable prodrugs are described in T. Higuchi and V. Stella's Prodrugs as Novel Delivery Systems, Vol. 14 of the ACS Symposium Series, Edward B. Roche, ed., Bioreversible Carrier in Drug Design, American Pharmaceutical Association and Pergamon Press, 1 987, and "Improved oral drug delivery: solubility limitations overcome by the use of prodrugs," published by D. Fleisher, S. Ramon, and B. Barbra, Advanced Drug Delivery

Reviews (1 996) 1 9 (2) 1 1 5-130, each document will be incorporated here as reference materials. 16 514938 200409756 A prodrug is any covalently bonded carrier that releases a compound of formula (I) in vivo when the prodrug is administered to a patient. Prodrugs are generally prepared by modifying functional groups, and the original drug is produced by routine manipulation or by breaking the modification in vivo. Prodrugs include, for example, compounds of the present invention in which a radical, amine, or weyl is bonded to any group, and when administered to a patient, it breaks to form a radical, amine, or sulfhydryl. Thus, representative examples of prodrugs include, but are not limited to, alcohols of compounds of formula (I), acetates of thiol and amine functional groups, formate and benzoate. In addition, in the case of a carboxylic acid (-COOH), an ester such as a methyl ester, an ethyl ester, a diester, or the like can be used. Esters can be hydrolyzed upon their own activation and / or in the body. Suitable pharmaceutically acceptable hydrolysable esters in the body include esters which are easily eliminated in the human body while leaving ortho acids or salts thereof. The compounds of the invention may be and / or may be administered in the form of a pharmaceutically acceptable salt. For comments on suitable salts, see Berge et al5 J. Pham. Sci., 1 977, 66, 1-19 °. Typically, pharmaceutically acceptable salts can be easily prepared using a suitable desired acid or base. The salt can be precipitated from the solution and collected from the eluent or recovered by evaporation of the solvent. Suitable addition salts are formed from acids and become non-toxic salts, examples of which are hydrochloride, hydrobromide, hydroiodate, sulfate, hydrogen sulfate, nitrate, phosphate, hydrogen phosphate, acetic acid Salt, maleate, malate, fumarate, lactate, tartrate, citrate, formate, gluconate, succinate, pyruvate, oxalate, oxalate, trifluoro Acetate, gluconate, benzoate, sulfonate, ethanesulfonate, benzenesulfonate and p-toluenesulfonate.

31493S 200409756 Medically acceptable alkali salts include ammonium salts, such as alkali metal salts of sodium and potassium, such as alkaline earth metal salts of calcium and magnesium, and organic alkali salts, including primary, secondary Z, and tertiary amine salts, such as isopropylamine , Diethylamine, ethanolamine, trimethylamine hydrazone, dicyclohexylamine and N-methylglucamine. In another aspect, the present invention also provides a step for preparing a compound of formula VII, which comprises the hydrolysis of a bitter vinegar derivative of formula (11):

ΟΙ) Here R] to R4, m, n, p, t, A, β, D, L,], Q, v, w, X, Y, and z are defined as in formula ⑴ and R is a carboxylic acid ester And then optionally forms a pharmaceutically acceptable derivative thereof. Examples of suitable R groups are c] 6 alkyl such as methyl or tertiary butyl. Hydrolysis can occur via acidic or experimental vehicles. This technique is familiar to artists. '[Embodiment] (Best Mode for Carrying Out the Invention) The compound of formula (II) can be prepared by: (a) Compound of formula (III) 314938 18 200409756

React with Z as defined by formula (I) or formula (II) with compound of formula (IV)

FG2 (R) (IV) Here R1, m and Q are as defined above and FG1 and FG2 contain suitable functional groups which can react together to form a urea moiety; or (b) define FG1 as NH2 as before Reaction of a compound of formula (III) with a compound of formula (V)

D

(V)

LG Here R], D and m are defined as in formula (I), Q and V combine to form a 5 to 7 19 314938 200409756 membered heterocyclic ring and LG is a leaving group. (c) the compound of formula (VI)

D

Here R], R2, R4, m, η, t, A, B, D, Q, R, V, W, X, Y and Z are defined as compounds of formula (I) or (II) and formula (VII) reaction

Here? , 11, 113,], 6 and 1 ^ are defined as in formula (1) or (11), where they are defined as before and LG1 is the leaving group. For step (a), suitable examples of suitable FG1 and FG2 include: (i) FG1 is -N = O0 and FG2 is NH2; or FG1 is NH2 and FG2 is N = C = 〇; or (ii) FG1 is NH2 and FG2 are NH2 and form a suitable agent with urea. The reaction of step (1) is typically performed at an ambient temperature in an inert solvent such as dichloromethane or acetonitrile. 20 314958 200409756 The anti-deer of step (ii)] ^ At ambient temperature or elevated temperature; ^ There are, for example, carbonyldiimidazole and formulae, such as dimethylformamide, four cases of lefenam, or Dichloromethane is inert and suitable solvents, such as ㊉φα Xiao 丨 'money cooling agent', and in the presence of, for example, -Γ its makeup ten ni + a. Let ⑴-ethyl month female or pyridine. For step (b), a suitable example for the production of 隹 j | iodoidyl is halogen ', especially gas. Examples of δHai Xun responses include white, +, and Ding examples included in the text of Jung et al. (J Med.

Chem., 1991, 34 ί3, ι ι Λ Ί -OC. 5 110 and Passerini (J. Chem 1954, 2256). · For step (c), leaving the eighth soil 5 is not halogen, especially the mouse 0 reaction is typically under the Cypriot Heihingdingshiren 乂 Λ * ”a, e.g. Tetrafuran or acetonitrile-based solvents. Intermediate compounds of formula (IΠ), (IV), (V), (VI) and (νπ) can be obtained from the following formulas: It is prepared by the technique of this method or a similar method. Those skilled in the art should understand that in the preparation of the compound of the present invention or a solvate thereof, it may be necessary and / or desired to protect one of the molecules or Multiple sensitive groups to avoid unwanted side reactions. Suitable thinner groups used in accordance with the present invention are those skilled in the art and can be used in conventional methods. See, for example, "Protective groups in organic synthesis" by TW Greene and PGM · Wins (John Wiley & sons 1991) or "PrOtecting

Groups "by PJ Kocienski (Georg Thieme Verlag 1994). Examples of suitable amine-protecting groups include fluorenyl-type protecting groups (eg, fluorenyl, difluoroethylfluorenyl, ethylfluorenyl), aromatic ethylamine Ester-type protecting group (for example, 314938 200409756 benzyloxycarbonyl (Cbz) and substituted Cbz), aliphatic carbamic acid ethyl-protecting group (for example,% oxoyloxycarbonyl fluorenylmethoxyxycabyl) Fmoc), the third 'butoxycarbonyl group [mu]), isopropoxycarbonyl group, cyclohexyloxycarbonyl group) and alkyl-type protecting groups (eg, benzyl, dibenzyl, chlorotriphenylfluorenyl). Examples of suitable oxygen protecting groups include, for example, alkylsulfanyl or alkyl-silyl of second-butyldimethylsilyl; such as tetrahydropyranyl or tertiary-butyl alkyl ether; or, for example Acetic acid = esters. The compounds of the present invention are tested for biological activity in vitro according to the following assays. Cells; Rapid Phosphorescence Flash; (Jurkat J6 Scintillation Proximity Assay; SPA) Tests using human lymphoblast J6 Rapid Phosphorescence Flash Assay Human lymph Interaction of integrin vla_4 (very late integration antigen-4; α4β1; CD49d, CD29) on the mother cell j6 cell membrane with the test drug. N-2-hydroxyethyl p-diazepine sulfonic acid ( N ^^ hydroxyethylpiperazine-N1 ^ .ethane sulfonic acid: HEPES) '100 mM sodium chloride and lmM manganese dichloride (pH adjusted to 7.5 with 4M sodium hydroxide). 10,000 cells / well) were mixed in wheat gerni agglutinin-coated SPA beads (Amershame, 1 mg / well). Titrated sH Standard Compound A (the final concentration of 1 to 3 nM) and The test compounds are dissolved in a suitable solvent and diluted with assay buffer. The compounds are measured in a single point (singHcate) operation using the four-parameter curve of equation ⑴. The equilibrium dissociation coefficient of each compound is calculated according to the method of Cheng & Prusoff. 22 314938 200409756 is shown to be pKi. Standard compound A is (2δ) _3_ [4 · ({[4_ (aminocarbonyl) hexahydropyridyl] -carbonyl} oxy) -phenyl] _2 _ [((22) _ Cardiomethyl_2 _ {[2Xingylphenoxy) ethenyl] amine } - pentyl acyl) amino] propanoic acid potassium salt thereof disclosed in patent No. wo 00/37444 (Glaxo Gr〇up companies, etc.). Titrated 'gull' organisms can be prepared using conventional methods. The d y equation (I) a-d 1+ (f) b = where a is the minimum value and b is the HU1 slope ’. For 与 and d, the maximum K and Λ are compared with the minimum value. There is no test compound in the presence of a potassium salt of the compound A.Q ". Fu Zili, Slgma Chemicals, UK, product number D2P). The data are expressed as average ρΐ (: 50.) According to this method, pKi 2 6_5 was obtained according to this method. The compound of formula (I) and JL shovel, Xinbayi, Xi Liang Lianwen received information on how organisms can inhibit "4 integrin cell adhesion and believe that it has potential as a treatment or prevention of the following conditions such as rheumatoid arthritis treatment or form Λ ,, (), filial piety, such as Zhi Yanzhi Allergies $, adult respiratory distress syndrome cardiovascular disease; blood two Alzheimer's disease; reocclusion; reperfusion injury Bao Bao small plate agglutination; blood test after dissolution and atopic skin ah silver shoulder disease 'wet therapy, contact Dermatitis and gastrointestinal diseases in men and women '· Diabetes (for example, pancreatic chrysanthemum -1 immune diabetes); Multiple sclerosis; Systemic Red King Lupus (SLE); For example, ulcer fire ^',, health, ⑺ know fire, Brother Wien's disease (localized 314938 23 200409756 θ person) and the intestinal sac Inflammatory bowel disease of pouchitis (for example, after rectal portal anastomosis): Except ::, entero-anal lymphocytic ... J arthropathy of joint disease, related to eosinophilic leukocyte gastroenteritis He such as skin, urine is associated with lymphocytic infiltration into it

= Birth / mastitis (breast); hepatitis, cholecystitis; cholangitis or bile ducts ::: and '' surrounding tissues); bronchitis and 1 sinusitis; interstitial pulmonary electrofire diseases, such as allergic Pneumonia, collagen disease (in all = lupus erythematosus and rheumatoid arthritis); sarcomatoid disease; osteoporosis X month joint ^ arteriosclerosis; including neoplastic metastasis or cancerous growth ^ biological disease 'trauma (trauma Treatment enhancement); certain eye diseases such as retinal detachment, allergic conjunctivitis and autoimmune uveitis; Sjogren's syndrome (Sjogren, syndromo); rejection after chronic liver transplantation (chronic and Acute); host-to-graft or graft-to-host disease; endothelial hyperplasia; arteriosclerosis (including graft arteriosclerosis after transplantation); percutane〇us coronary angl0plasty in, for example, percutaneous cavity; PTCA) and post-embolization or restenosis after percutaneous transluminal arterial recanalization; nephritis; tumor angiogenesis; malignant tumors; multiple myeloma and osteoma-induced bone resorption; sepsis; and for example Stroke, Traumatic brain injury and spinal cord injury and central nervous system injury in Meniere ’s disease. The compounds of the present invention are preferably used for the treatment or prevention of asthma, such as allergic conditions such as rhinitis, such as ulcerative colitis and Crohn's disease 200409756 inflammatory bowel disease, rheumatoid sclerosis and organ transplantation 1 Exclusion. A * Orthotopic dermatitis, multiple modulation = further provided-a safe and effective amount of a compound of formula (I) for the treatment or prevention of a condition beneficial to α σ ρ, an old inhibitor of 4 'patients :: : 'There is a need for a method of treating or preventing the aforementioned conditions. %% is specially provided-the invention also provides a compound of formula (I) or a pharmaceutically acceptable derivative thereof, for use in ... treatment, especially for the treatment of the aforementioned diseases. In a 4 :: viewpoint, the present invention provides a compound of formula (I) or a medicinal product thereof. (2) The use of a biological agent for the production of a disease or preventive agent that is beneficial to α4 regulating cell adhesion, especially the aforementioned diseases. The sensible compound can be administered alone, but is preferably root =: and _ is a pharmaceutical composition. Therefore, the present invention also provides a medical method, and the product contains a mixture of a carrier and a diluent. The amount and a pharmaceutically acceptable method, which is an acceptable derivative. The present invention further provides a preparation method comprising mixing at least one compound of the present invention or a medicament thereof with a medically acceptable carrier or diluent.

"The composition can be used on humans and animals in humans and animals, and it can be used in humans or animals and typically contains 乂 仁 # _ p — south. More or less Shilo acceptable diluents, carriers or excipients J W's therapeutically acceptable carriers or diluents are well-known in medical technology and described in 仏 丨 丄 D ·

Sciences, Μ Pharmaceutical carriers, such as Pharmaceu tlca j ack Publishing Co. (AR Gennar edit. 1 985) by Rennngton ° Selection of excipients or diluents can be based on the intended route of administration and the standard pharmaceutical method of 314938 200409756 The choice of firefly-carrying limbs or thinner should be accessible, and there will be no gold for its recipients. "More overflowing" means again and again. Carlo acceptable carriers or diluents are good, such as binders (for example, Tangrang, Gum Arabic, Mingsheng, Sanli, for example «, polyethylene tetrahydro one), job type agents (for example: = yellow corn Starch, Potassium Phosphate, Mountain ¥ $, Caramel,

Magnesium acid, talc, polyethylene glycol di 4 :) 'lubricants (... humectants (such as sodium lauryl sulfate), etc. (e.g. potato potato powder),: dosing route (conveyance) of the composition of the invention Includes, but is not limited to: a variety of oral (such as tablets, capsules, or ingestible solutions), topical 'mucosal (such as nasal spray type + Yitiao Beizhao or inhalable spray) ), Nasal, non-oral (e.g. by injection; month% •, intraspinal, intraperitoneal, intramuscular, intravenous, intrauterine, intracellular, intraocular, intradermal, Inside, inside the trachea, inside the vagina, inside the cerebellum, inside the brain, underneath the eyes (including the vitreous or the ciliary body), the skin, the rectum, the cheek # epiglottis, the sublingual. For example The compounds can be administered orally in the form of tablets, blistering, ovules, brews, solutions or suspensions, which may contain flavors or tinctures, as an immediate delayed-, modified-, supported pulse -Or controlled release applications. Tablets may contain, for example, microcrystalline cellulose, lactose, sodium citrate, carbon Excipients of calcium acid, calcium hydrogen phosphate and glycine, such as starch (preferably corn, potato, or cassava starch), starch glycolate sodium salt, crosslinked carboxymethyl cellulose sodium (croscarmejjose sodium) and certain complex silica disintegrants, and for example polyethylene tetrahydropyrrolidone, hydroxypropyl cellulose (HPMC), propyl cellulose (HPC), recommended sugars, gelatin and Arabic Granulating adhesive for gums. In addition, it can include, for example, magnesium stearate, stearic acid, glycerol 200409756 docosanoic acid and talc grease. Similar typical tincture compositions can also be used as fillings for gelatin capsules. And preferred excipients include lactose, powder, cellulose, milk sugar or high molecular weight polyethylene glycols. For aqueous suspensions and / or elixirs, the medicament can be combined with a variety of sweet or flavoring agents, colorants or Dyeing agents, and emulsifying and / or suspending agents, and diluents such as water, ethanol, propylene glycol, and glycerin, and combinations thereof. The compounds of the present invention can also be ground using conventional grinding procedures such as wet grinding to obtain suitable As tablets and suitable as other formulations The particles are large] The finely divided treasures of the compounds in this volume (preparation of the semi-private worker's feather knife d (not rice particles) can be prepared by the procedure of Bai Zhinong's technology, such as n9 / nnlo ^ c. No. w〇〇2 / 00196 (SmithKline Beecham). When the compound of the present invention is administered parenterally, such administrations include: multiple types: intravenous' intra-arterial, intraperitoneal, intraspinal: wide Intra-uterine, intracranial, intramuscular, intramuscular injection of the drug; and / or use of infusion technology. For non-oral, the best form of use of the compound is ^ Water and quality, for example, ample 1 3 can have other substances I, or glucose, so that the aqueous solution and blood. When necessary, water, Xuan Zang A Wenma Zhangzhang / liquid C 3 is properly buffered (Preferably 9). The preparation of a non-oral formula of 3 to mouth suitable combined under aseptic conditions is easily accomplished by standard medical techniques known in this technology. 3 As described by Bai, the administration of this material in the Ming dynasty 1 j Maoyue β can be administered intranasally and it is conveniently round g π 4 said to be transported by suction as a dry powder inhaler or by Pumps, sprayers or use, such as two-disease _ β-gluten, lice monoflurane, difluorofluorocarbon P monochlorotetrafluoroethane, such as J ^ oyster, difluoroethane (HFA 134ΑΤ ,,,, ,) Or 3) 4938 200409756 1, M, 253, 3, 3_ Heptafluoropropane (HFA 227EA) (Hiroda Inneos

Fluor), carbon dioxide or other suitable gases. In the case of pressurized spray, the dosage unit can be determined by measuring the amount provided between rounds. Pressurized containers, systems, nebulizers or inhalants = solutions or suspensions of active compounds, such as a mixture of ethanol and propellant ^, which may additionally contain a lubricant such as sorbitan trioleic acid S purpose. Capsules or canisters for poetic inhalers or inflators (eg:

Made of gelatin) may be formulated as a powder mixture containing the compound with a powder base such as lactose or gluten. σI or 'The compounds of the present invention can be administered as anal suppositories or vaginal suppositories, or they can typically be applied as coagulants, hydrogels, emulsions, solutions, oils or powders. The compounds of the present invention can also be applied either dermatologically or transdermally: for example, by a skin patch. It can also be administered by the pulmonary or or rectal route. It can also be administered by the eye path. For ophthalmic use, the compound can be formulated as a fine suspension in sterile physiological saline such as physiological PBS + inch concentrated PBS, or, preferably, as a solution in whole sterile saline. It is necessary to combine the oral fertilizer 4benzyl chlorocarbamate (benzy) alkanonium chi state agent. Formula Benpo, ^ ^, /, can also be formulated as an oil agent such as vaseline. For the main application to the skin, The medicament of the present invention can be formulated as a suitable oil agent containing a compound of the formula, and the active compound is suspended or dissolved in, for example, a mixture of one or more of the following: mineral oil, liquid petroleum jelly, white spirit, petrolatum Or water. Or, it can be formulated as a compound, or hydrolyzed, for example, one or more of the following Π4938 28 200409756 compounds: mineral oil, sorbitol monostearic acid Two soils, polysorbate sixty, liquid limb rock-based dodecyl alcohol, benzyl alcohol, and water. The composition of the present invention can be administered by direct injection. In a preferred embodiment, the agent of the present invention is Systemic, buccal (under the tongue), Preferably it is oral. 'Thus' the preferred medicament is suitable for oral delivery. Typically, the physician will decide the actual dosage to make it more compatible. For any particular I # t ^, the unique dose concentration and frequency variation of a unique U-line mouth will depend on a variety of factors, which will be modified ^ including the metabolic stability of the specific octabutane compounds used Sexual and normal health conditions, gender, diet,… 1 long "age, weight, and the form of β before the rate of washing, combined with the drug, the severity of the disease / T, the rate of excretion for the human economy Mouth and skin II: For individual treatment in progress. Single or divided doses. For daily doses of the medicament, the compound of the present invention can be dosed to humans based on the weight of free base to dry limb weight) Administered ~ lining is not (^ mg is per unit dose! Mg to 500 mg 'is preferably administered, for example, ^ to 4 u field / day / knife per day. The unit dose is perceptible It may be necessary to depend on the route of grant. There is a routine variety of doses depending on the severity of the route ... The route. The precise dose and route of administration are ultimately == free choice of administration. The compounds of the invention may also be combined with other compounds It is used in combination. Therefore, 314938 200409756 The present invention provides a 'further view, a composition comprising the compound of the present invention or a pharmaceutically acceptable derivative thereof and other therapeutic agents. When the compound of the present invention or a pharmaceutically acceptable derivative thereof and Active Confrontation = When used in combination with a second therapeutic agent for a disease, the dosage of each compound will be different from that when the compound is used alone. The appropriate dosage will be easily managed by those skilled in the art. The required amount of the compound of the invention for treatment will vary depending on the nature of the condition to be treated and the age and condition of the patient ', and will ultimately be freely chosen by the visiting physician or veterinarian. Other active agents that can be combined with the compound of formula ⑴ Examples include, but are not limited to: (:) other VLA_4 antagonists; (b) m histamine antagonist Qi " non-steroidal anti-inflammatory and analgesic (NSAID); anti-diabetic agents such as gliptin = Z: S) Ve) Anti-B-bile biliary test agents; ⑴epoxidized enzymes_2 alcohols, for example, (heart ^ acid two § intent enzyme W ^ preparation; ㈨ steroids, ... — CCR_8J = drug for sclerosis For example, interferon; antagonized by two :: can = (LFA-1) antagonize Qi j. Knife this related antigen] and because of the convenient use of pharmaceutical formulas plus "realizing agent's pharmaceutical formula is included in the other of the present invention-View II ; "Individual ingredients can be administered sequentially or simultaneously in separate or combined = ^ sweat therapy any better path. When it is administered sequentially, 'this hair = formula by or the second therapeutic agent can be x compounds For the same or different pharmaceutical composition = I: For simultaneous administration, 3 ^ 938 30 200409756 When combined in the same formula, the other components of the formula are provided in a stable and any convenient formula, in the form of custom. It should be noticed that two The compounds must be compatible with each other. When the formula is separated, it can be known about the convenience of the compound in this art: there are reports, including but not limited to patents and patent applications, which will be combined here. ^ Yf is Cangkao literature and when individual reports are special Local people were individually disclosed in the text, and those who entered "Wang Wen" will be incorporated in the text as reference 0. The following production examples and examples will explain the compounds of the present invention in more detail. Production Example 1: 3- (4-Nitrobenzene ) Pyridine (ρι) I, 1-bis (dibenzylphosphino) bis (cyclopentadiene) ferrous dichloropalladium (III) (0.2 g 'G.2 mmol) Stirred and degassed bromoyl benzene (5 g, 24.8 mmol) and pyridin-3-boronic acid (3.4 g, 27.2 mmol) in difluorenylamine (5 〇mL) and 2N sodium carbonate solution in water (20mL), the reaction mixture was stirred at 100 C for 18 hours, and then cooled. The solution was passed through diatomaceous earth (Cente; Diat. Maceous Earth) After filtration, ethyl acetate (200 ml) was added, and the organic phase was washed with brine (200 ml). The organic phase was dehydrated (anhydrous sulfuric acid) After concentration, the title compound was obtained as a solid by purification by silica gel chromatography (30/0 v / v ethyl acetate in petroleum ether). Production Example 2: 3- (cardio-nitrophenyl) oxidine-p-oxide ( P2) Slowly add m-chlorobenzyl peroxyacid (6.9g, 40.0 mmol) to 3_ (4-sodium phenyl) roar (P), 4g, 20.0 mmol) in tetrahydrofuran (200 The reaction mixture was stirred at room temperature for 1 hour. The solution was poured 3) 4938 200409756 into an aqueous solution of sodium thiosulfate and the resulting mixture was concentrated. The title compound was obtained after trituration with ethyl acetate. Production Example 3 · 3-(4 -Shi Xiao Phenyl) -1 π pyridine-2 -one (ρ 3) will be 3- (4_nitrophenyl) pyridine-1 —oxide (P2,2 · 5 G, 116 millimoles) was refluxed in acetic anhydride for 18 hours, and then cooled. The reaction mixture was waved and concentrated hydrochloric acid (25 ml) was added. The solution was stirred at reflux for 4 hours.

Then cool down. The reaction mixture was poured into ice / water, filtered and dried under high vacuum to give the title compound as a solid. Production Example 4. 3_ (4 ~ fluorenylphenyl) ethyl acetate (ρ4) 4-bromobenzyl alcohol (10.5 g '5 "millimolar), triphenylphosphine (0.5 g, U Mmol) and palladium acetate (0.5 g, 2.2 mmol) in ethyl acrylate (20 ml) and triethylamine (100 ml) with stirring and refluxing for 72 hours, and then cooled. The reaction mixture transitions through diatomaceous earth Then, it was concentrated. The crude solid was purified by Shixi knee chromatography (hui ν / ν ethyl acetate in petroleum noodles) to obtain the title compound as an oil. Production Example 5: 3- (4-hydroxyfluorenylphenyl) Ethyl propionate (ρ5) (4 fluorenylphenyl) acetic acid ethyl acetate under a hydrogen atmosphere pressure palladium (0.3 g) in ethanol (30 mixture through diatomaceous earth to obtain an oily title compound (P4 , 3 grams, 1 4.5 millimoles) and activated carbon (4 milliliters) and stirred for 4 hours. The reaction (Diatomaceous Earth) was filtered to concentrate 0 Manufacturing Example 6: 3-Hydrochloromethylphenyl) ethyl propionate Sulfuryl chloride (16 units of 4 at 4 a gross liter, 209 mmol) was slowly added to ethyl 3- (4-hydroxyfluorenylbenzyl) propionate (p5 ~ · 9 g) ] 3.9 耄 Mo Er) in the third month 314938 200409756 base month Female students (4.0 liters, 27.8 millimoles) and: chloroform & (30 ml) of the mixed / mixed liquid side, the solution was stirred under the dish for 18 hours, and then with 1N hydrochloric acid aqueous solution Wash the solution. Dehydrate the organic phase (concentrate anhydrous chicken with sulfuric acid to give the title compound as an oil. Example 1 7.3 {'[3-Ga4-Nitrophenyl) -2_keto_27 / _pyridine_1_yl Fluorenyl] phenyl} ethyl propionate (P7) Under room temperature, 3-gas 4-nitrophenyl) -177-pyridin-2-one (P3, 200 mg, 0.93 moll), 3- Ethyl (4-chlorofluorenylphenyl) propionate (p6,270 mg, 1.20 pen moles) with carbonic acid (900 mg, 2.78 mmol) in dimethylformamide (5 ml ) And stirred for 18 hours. The reaction mixture was filtered through celite (Dxatomaceons Earth), concentrated and purified by silica gel chromatography (50 / 0v / v ethyl acetate in petroleum ether) to obtain the title compound as a solid. Example 8 · 3- {4- [3- (4 · Aminephenyl) -2_ketopyridine-butylmethyl] phenyl} propanoate (P8) at room temperature under hydrogen ambient pressure Put 3_ {4_ [3_ (4_nitrophenyl) _2monomethyl-2, crocodile bite-1-ylyl] benzyl} c Ethyl ester (P7,300 mg, 0.74 tmol) was stirred with palladium (30 mg) on activated carbon in ethanol (10 ml) for 3 hours', and then the reaction mixture was filtered through celite and concentrated. The crude The oil was purified by silica gel chromatography (50% v / v ethyl acetate in petroleum ether) to give the title compound as an oil. Production Example 9: 3- (4- {2-keto-3- [4- (3 -O-Phenylphenyl-ureido) phenyl] -2 / ^ mouth ratio ° 疋 -1 -ylmethyl} phenyl) propionic acid ethyl ester (p9) at room temperature will be 3-{'[3- (4-Aminephenyl) -2-keto-21pyridylfluorenyl] benzyl) ethyl propionate (P8, 60 mg, 0.16 mmol) and isocyanate 31938200409756 o-pyrenyl ester ( 40 μl, 0.32 mmol) were stirred in dichloromethane (5 ml) for 3 hours, and then the reaction mixture was concentrated. The title compound was obtained after trituration with ethyl acetate. Production Example 10: 3- {4- [3- (cardiacinyl) -5-chloro-2, yl-2 //-D ratio. Ding_1 meridyl] phenyl} ethyl propionate (P 10) Add acetic acid (1 liter) and subsequent iron (160 mg, 2.9 mmol) to 3- (4- [5 -Chloro-3- (4-stone phenyl) -2-g isopropyl-277-D ratio. Established _1_synmethyl] phenyl) -ethyl propionate (0.31 g, 0.72 mmol) In a solution of ethanol (10 ml) and water (5 ml). The mixture was heated under reflux for 2 hours and then cooled from σ'P to 'warm. After gas-water analysis, the mixture was filtered through a pad of Diatomaceous Earth and the filtrate was evaporated to dryness. The residue was placed in an aqueous solution of sodium bicarbonate / ethyl acetate, and the organic phase was washed with brine, dried over anhydrous sodium sulfate, filtered and evaporated to dryness. Passing from 30 to 50 ° /. Silica gel chromatography on a gradient of ethyl acetate in hexanes afforded the title compound as an oil. Production Example 11: (±) -3- {4- [3- (4-Aminophenyl-2-keto-2 / 7-pyridine-butylmethyl) benzyl] butyrate (P1 1) A solution of sodium borohydride (0.CM2 g, 1. 丨 mmol) in nickel hexahydrate (0.088 g, 0.37 mmol) in methanol (15 ml) at room temperature The mixture was stirred for 30 minutes, and then (E) -3- {4_ [3j4_nitrophenylketo-2-orbitidine-phenyl] phenyl} butenoic acid methyl ester (0.3 g, · 74 pen moles) in methanol (10 ml). An additional portion of sodium borohydride (0.098 g, 2.59 mmol) was added and stirring was continued overnight. An additional portion of rotten sodium hydride (0.15 g, 3.96 mmol) was then added to complete the reaction. The mixture was filtered through celite, washed with methanol (50 ml), and the filtrate was concentrated in vacuo. The residue was extracted with chloroform (2 x 50 ml) and the organic phase was washed with water (20 ml). The organic layer was dried over anhydrous magnesium sulfate, filtered and evaporated to dryness to give the title compound as an oil. For the aforesaid synthesis, (E) -3- {4_ [3_ (4_nitrophenylketo_2_sn.dio-i-yl] phenyl} but-2-enoic acid methyl group is composed of p3 and ⑻_3_ (4-Methanesulfonyloxymethylphenyl) but-2-enoate was prepared according to the method of Production Example 7, and (E) -3- (4-methanesulfonyloxymethylphenyl) butyl The _2_enoic acid methyl ester was prepared from (E) -3- (4-methylphenyl) butane-2-methenoate and methanesulfonyl chloride in a similar manner to that of Production Example 6 (in this case Most of the preparation is mesosulfonyl ester instead of chloroacetic acid). (EL3 # -Methylphenyl) but-2-enoic acid methyl acetic acid is prepared by bromobenzyl method according to the method of "Member 4". Preparation of alcohols and methyl butenoates. Example 11a. (±) _3_ (4_ {2_keto_3_ [4_ (3-methyltolyl-ureido) phenyl] 2 Methyl phenylphenyl) methyl butyrate (p 丨 The title compound consists of (±) _3_ {4_ [3_ (4_aminophenyl_2_keto_2uglyl_pyridin-1-ylmethyl) phenyl ] Butyrate (P1 υ and o-phenylene isocyanate were prepared by the method of Production Example 9. Production Example 1 2 ·· 1-"3-if 4 f Ο W e nir L Both 4 — (2- Lactopyridine-3-yl) benzyl] -3-o-toluene urea (P12) will be 1,1 ，-双 f-# ## #, and (a Benthophosphino) bis (cyclopentadiene) ferrous dichloropalladium (11) ^ 0.1 g) was added to the stirred and degassed 1-. ( 4-bromo-3-fluorophenyl > 3-o-metamorphine urea (0.5 g, 5 mmol) and 2-methoxypyridin-3-ylboronic acid (258 mg, 1 7 (Taiwan • Mao Wuer) in a solution of dimethylformamide (10 ml) and sodium carbonate water bath in 7 丨 (Chinese "black ~ (pen liter, 2N). The reaction was mixed at 100 DC

3] The 493cS compound was stirred for 18 hours, ~ (75 ml) and the organic di-main compound was finely mixed with ethyl acetate (anhydrous magnesium sulfate), and washed with water (3 x 75 ml). The organic phase was dehydrated with ethyl acetate in hexane ^ θ and chaotically (20 to 40 ¾ v / v B MSiES +,) to give the title compound as an oil.

MS (ES + Ve): [M at m / z 352). m requires [M + H] + 4- (2-keto di) Production Example 13: 1- [3 ~ fluoro o-toluene urea (Pl3) hydropyridin-3-yl) phenyl] -3-

1- [3-Fluoro, 4- (P12) (0.150 g) was stirred and refluxed for 8 hours. The title compound D (1methoxypyridin-3-yl) phenyl] _3_o-pyrrolidine 0.43 Pen Moore) The reaction mixture was cooled in ethanolic hydrochloric acid (10 ml), and then concentrated to obtain a solid m / z 338 (C) 9H] 6FN302 requires [Μ + Ή] + MS (ES + ve): [M + H] + ^ at m / z 3 3 8). Manufacturing Example 14:. , # ((5) -2-Ethyl_ι_phenylethylaminofluorenyl) el · (Azulenylethyl) -ethyl benzoate (P14) Tritium oxalate (3.9 ml, (45 mmol) to 4- (2-carboxymethylmethacone) (JL DeGraw w α /. / · C /? Ew. 1 986, 29 1〇56) ( 3.54 g, 15 mmol) in dichloromethane (100 ml) in an ice-bath cooled solution. Dimethylformamide (0.1 ml) was added and the mixture was allowed to drain at room temperature for 2 hours. And then concentrated under reduced pressure. The residual acid chloride was dissolved in dichloromethane (60 ml) and added to (S) -2-phenylglycine (2 72 g, 2 〇mmol)) and ice-cooled mixture of triethylamine (63 ml '45 Amol) in dichloromethane (60 ml). 36 314938 200409756 The reaction mixture was stirred at room temperature for 1 hour. 2N hydrochloric acid was added, and the organic phase was separated, then washed with water, dehydrated (anhydrous magnesium sulfate), and evaporated. The non-mirrored product was flash-chromatographed with ethyl acetate and then ethyl acetate-methanol (9: 1). ) Elution and separate. Get earlier elution Mirror isomer (pl4a), thin layer chromatography (silica gel; ethyl acetate) &〇36; Μ§ (Εδ + ν ^: [M + H] at m / z 3 56 (C2) H25N〇4 Requires [M + H] + at m / z 356); and the non-mirror isomers (pi4b) of the elution (AS) of scutellariae; thin-layer chromatography (silica gel; ethyl ethyl acetate) Rf is 0.19 MS (ES + ve) ·· [M + H] + at m / z 356 (C2] H25N04 requires [m + h] + at m / z 3 56). 1Case 15: 3- (i? And Cardiac hydroxymethylphenyl) _1 ^ ((^ 5> 2-hydroxyphenylethyl) -butanamide (Pl5a and P15b) Lithium borohydride in tetrahydro Dfuran (2M, 15 ml, 30 mmol) Mol) was added to a solution of the later eluted non-mirror isomer (pi4b) (2 42 g, 6 81 mmol) in tetrahydrofuran (1000 ml). Add 曱After 3 seeds (1 liter), the reaction mixture was stirred at room temperature for 2 hours. Another portion of lithium borohydride was added in tetrahydrofuran (2M, 10 ml, 20 mmol) and methanol (0.88). The mixture was stirred for another 3 hours, and then cooled in an ice bath. After carefully adding 2M hydrochloric acid (100 ml), the mixture was concentrated under reduced pressure. Ethyl acetate was added and the organic phase was washed with water, then washed with brine, dehydrated (anhydrous magnesium sulfate) and evaporated to give the title compound (i? Phantom non-mirror isomer (PI 5b); MS (ES-ve) : [Μ-Η] 1 m / z 312 (C) 9h23n03 requires [Μ-ΗΓ at m / z 3 12). The non-mirromeric isomer (p15a) was prepared in a similar manner from an earlier eluted non-314938 200409756 mirror isomer, P14a. Production Example 16: (7?)-(+ (4-hydroxyfluorenylphenyl) butyric acid methyl ester (P16)

3N sulfuric acid (85 mL) was added to a solution of the non-mirromeric isomer Pl5b (2 g, 6.38 mmol) in dioxane (85 mL). The mixture was heated under reflux for 6 hours, then cooled and concentrated under reduced pressure. The concentrated solution was extracted three times with ethyl acetate, and the combined organic phases were washed with water and then with brine, dried (anhydrous magnesium sulfate) and evaporated. The residual solid was dissolved in methanol (90 ml) and concentrated sulfuric acid (2 ml) was added. The mixture was refluxed for 1 hour, and then concentrated under reduced pressure after cooling. Water and ethyl acetate are added organically; 1 mesh is washed with water, then washed with brine, dehydrated (anhydrous magnesium sulfate) and evaporated. Using this, & α ... 丄 丄 乂 远 chromatographic purification and elution with ethyl acetate-hexane (1: 1) to obtain the title compound of ..., color oil; [a] D30, 41.2. (C, methanol). Production Example 17 ··· The title compound was prepared from methyl methylphenyl) butyrate methyl SI (P17) as Pl5b; [the method aimed at Production Example 16 was prepared from non-mirror isomerization w (RH,) D / + 42-4 ° (c = 1.0 'methanol). Phenyl] -m; u-based °, (4- {2-keto-3- [4- (3-o-tolylureido) at 0. First, 1 methylphenyl) butyrate Esters (P18) Methanesulfonyl chloride (0.16 to ^ ethylamine (0.3 ml, 0.22 mmol), then (0.4 g, 1.92 mmol, 2. Mol) was added to P16 The resulting product mixture was stirred for 2 hours, a solution in lactam. Mix at 0 ° C and then use k, main, and hair. The resulting formazan * was washed with water, dehydrated (anhydrous magnesium sulfate), and then steamed, and then added] ~ f4 I cold afternoon ash monomethylformamide (20 ml) 2 g of phenyl urea (0 · 6) Soil, 2''a monopyridyl) phenyl ortho-92, mol) and palladium carbonate (). 25 g, 384

3] 493S 38 200409756 millimoles). The mixture was stirred at room temperature for 3 hours and then concentrated under reduced pressure. The residue was separated into ethyl acetate and water, and the organic phase was washed with water, then washed with brine, dried (anhydrous magnesium sulfate) and evaporated. Purification by flash chromatography and elution with an ethyl acetate-toluene mixture gave the title compound as a colorless gum; [a] D26 ° C-17.2. (C = 0.5, methanol); MS (ES + ve): [M + H] + at ιτι / ζ 510 (C3] H31N304 requires [M + H] + at m / z 510). Production Example · (5) ((+)-3- (4- {2-keto-3- [4- (3-o-pyridylphenylureido) phenyl] pyridyl-1-ylpyridyl Phenyl) butyrate (pig) The title compound was prepared from p7 in a similar manner to P 1 8. [a] DJOc +1 7.0 (c = r0.5, methanol); MS ( ES + ve): [M + H] + at m / z 510 (C31H3) N304 requires [Μ + ΗΓ at m / z 510). Production Example 20: 4- [2-ethoxyhexylethyl] benzene 4- (2-carboxyethyl) phenylboronic acid (4 g, 20.6 mmol) in ethanolic hydrochloric acid under reflux for 24 hours. The reaction mixture was cooled and then concentrated to obtain The title compound was obtained as an oil. Production Example 21: 3- (4-pyridin-3-yl-phenyl) propionic acid ethyl ester (ρ21) 1,1′-bis (diphenylphosphino) bis (cyclopentane) Ene) Palloferrous chloride (11) (0.1 g '0.1 mmol) was added to the stirred and degassed 3_ Mohou bite (1.5 ml, 15.6 mmol) with 4- [2-ethoxy Carbonylcarbonylethyl] phenylboronic acid (P20) (3.5 g '15 .8 mmol) in dimethylformamide (30 ml) with 2N sodium carbonate solution in water (15 ml) . Under the work 00〇 ^ The mixture was allowed to cool for 18 hours' and then cooled. The solution was filtered through iron-aluminum tetraacid crushing, then ethyl acetate (100 ml) was added and the organic phase was washed three times with brine (100 ml). The organic phase was dehydrated (anhydrous) Magnesium acid), concentrated, and chromatographed with crushed gel 314938 39 200409756 (30% v / v ethyl acetate in paraffin ether) to obtain the title compound as an oil. Production Example 22 · 3_ [4 · (ΜΜ (ι_2,3-dihydroindolylmethylamido) amino] phenylphenyl 2-keto-21¾pyridin-1-ylmethyl) phenyl] propionate (P22) at 0C The 3, {button [3 彳 甲 aminophenyl) _2_ ketopyridine

A solution of methylmethyl] phenyl} propionate in tetrahydrofuran (5 ml) was added to triphosgene (0.135 g, 0.45 mmol) in tetrahydrofuran (5 ml ^). The solution was stirred. After 2 hours, a solution of indole (0.054 g, 0.45 mmol) in tetrahydrofuran U.5 ml) was added, and the mixture was continuously stirred at room temperature for 18 days. The ester (25 ml) was sequentially washed with hydrochloric acid (10 ml, 1M), washed with saturated carbon, and then dehydrated with anhydrous magnesium sulfate. The silica gel chromatography was increased from 1: 1 to 3: aqueous sodium hydrogen acid solution (10 ml) and brine, filtered and evaporated to dryness. The residue was subjected to a gradient of 1 ethyl acetate to hexane to obtain the title compound as a solid.衣 & Example 2j · (Ethyl-keto-o-benzyl-ureido) phenyl] • Hexahydro-1- (1-methylmethyl) benzyl) _ethyl propionate (P23) under ambient pressure (E) -3- {3- [3- (Heartylnitrophenyl-2_one group mouth ratio σ 疋 -1-ylfluorenyl) benzyl] acetate (85 mg, ο ·) Millimolar) and 10% activated carbon were hydrogenated in ethanol (20 ml) for 18 hours. The reaction mixture was filtered through calcium iron tetramerate, evaporated to dryness, and then purified by silica gel chromatography, eluting with 70% ethyl acetate / paraffin ether to obtain the title compound as an oil. MS (AP + ve): [M + H] 1 m / z 38] (C23h28N2〇3 f is [μ + η] + at m / z 3 8]) 〇3) 4938 40 200409756 Manufacturing Example 24: 3- {4- [3- (cardio-nitrophenyl) 4-keto-2 //-pyridin-1-yl] phenyl} ethyl propionate (P24) Ketone (P3) (0.2 g, 0.92 mmol), copper acetate (11) (0.3 34 g, 2 eq), diisopropylethylamine (0.3 ml, 2 eq), and Pyridine (0.15 ml, 2 eq.) Was added to a stirred solution of 4- (2-ethoxycarbonylethyl) phenylboronic acid (0.308 g, 1.3 mmol) in dichloromethane (10 ml). The reaction mixture was stirred under argon at room temperature for 4 hours. The solution was then filtered through calcium iron aluminum tetraphosphate, concentrated and purified by silica gel chromatography (50% v / v ethyl acetate in hexane) to obtain The title compound was obtained as an oil. MS (ES + ve): [M + H] + at m / z 393 (C22H20N205 required [M + H] + at m / z 3 9 3) Example 1 ·· 3- (4- {2-keto-3- [4- (3-o-pyridylphenyl-ureido) phenyl] pyridine-boxymethyl} phenyl) -propionic acid (El)

3- (4] 2-Keto-3- [4- (3-o-pyridylphenyl-ureido) benzyl] -2dandanol-1 -ylpyridyl} benzene at 60 ° C ≫ Ethyl propionate (p9, 55 mg, mol) and lithium hydroxide (50 mg, 25 mmol) were stirred in tetrahydrofuran (5 ml) and water (5 ml) for 30 minutes The reaction mixture was acidified to pH with 1N aqueous hydrochloric acid and then extracted with ethyl acetate. The organic layer was dehydrated (anhydrous acid-resistant magnesium) and evaporated to dryness to give the title compound as a solid. 41 314938 200409756 1H NMR δ (DMS〇-d6 ): 2.21-2.27 (5H, m), 2.73-2.80 (2H, t), 5.12 (2H, s), 6.28-6.34 (1H, t), 6.89-6.95 (1H, m), 7.12-7.25 (6H, m), 7.51-7.63 (5H, m), 7.68-7.77 (2H, m), 9.28 (1H, s), 10.47 (1H, s). MS (APCI-ve): [M] m / z 481, [MH] _ at m / z 480 (C29H27N3O4 requires [M-Η] · m / z 480). Example 2: 3- (3- {2-keto-3- [4- (3-O-pyridylphenylurethane) phenyl] -2 / 7-pyridine-boxyfluorenyl} phenyl) -propionic acid (E2)

The title compound was prepared using procedures similar to those of Example 1. MS (ES + ve): [M + ΗΓ at m / z 482 (C29H27N3 04 requires [M + H] + at m / z 482). Unless otherwise indicated, the examples listed in Table 1 are similar to Prepared by the method of Example 1. The steps of the change are described in the following examples E7, E9, E11, E23, E30, E31, E32, E34, and E35. 3M938 200409756

Example R1 R2a R2b R4 L JC〇2R Observed * [Μ + ΗΓ or [Editor or M · E3 2-Me HHH CH2 4-OCH7CO2H 484 E4 2-Me HHH (CH?) 7 4-CO? H 468 E5 2-Me OMe HH CH2 4- (CH2)? C〇2H 512 E6 2-Me HHH CH2 3-OCH? C〇2H 484 E7 2-Me HH 5-CI CH? 4- (CH2)? C〇 2H 516 E8 2-Me HHH CH2 4-C02H 454 E9 2-Me HHH CH2 (±) -4-CH (Me) CH2CO2H 496 E10 2-Me HHH CH2 (soil) -3-CH (Me) CH2C? H 496 E11 2-Me H H H CH? 4-NMeCH? CO? H 497 E12 2-Me OMe H H CH2 (±) -4-CH (Me) CH2C〇? H 526

43 14938 200409756

E13 2-Me HHH CH2 4- (CH?)? C〇2Me 496 E14 2-Me HHH CH2 3-NMeCH? COpH 497 E15 2-Me HHH CH2 4- (CH?)? C〇2Et 510 E16 2-Me HHH (cm? O 4-C02H fM-Hl'482 E17 2-Me HHH CH2 4- (CH2) 2C〇2 CH7OC〇2〇yc-Hex 638 E18 2-Me HHH CH2 4 > (CH2) 2 C〇2CH2 〇C〇2iso-Pr 598 E19 2-Me HHH CH2 4- (CH2) 2 C〇2CHp〇Ac 554 E20 2-Me HHH CH2 4- (CH2) 2〇〇2iso-Pr 524 E21 2-Me HHH (CH ?)? 3-CH? CO? H 482 E22 2-Me HHH (CH?)? 4-CH2CO2H 482 E23 2-Me HHH CH2 (± > 4-CH2CH (NHAc) CO2H 539 E24 2-Me HHH CH2 3 -CH2CO2H 468 E25 2-F 〇Me HH CH2 4- (CH2) 7C〇2H 516 E26 HHHH CH2 4- (CH?) PCO? H [M-HV 466 E27 2-FHHH CH2 4- (CH?)? C 〇2H 486 E28 2,3-diF HHH CH2 4 »(CH2)? CO? H 504 E29 2-Me-3-FHHH CHp 4- (CH?)? C〇2H 500 E30 2-Me HFH CH2 4- ( CH2)? Co2H 500 E31 2-Me HHH CH2 (SH +)-4-CH (Me) CH2CO? H 496 E32 2-Me HHH CH2 (R)-(-)-4-CH (Me) CH2C〇? H 496 E33 2-Me HHH CH2 (M-CH (Ph) CH? C〇9H 558 E34 2-Me HHH CH2 (S)-(+)-4-CH (Et) CH2C〇? H 510 E35 2- Me HHH CH2 (R)-(-)-4-CH ( Et) CH? CO? H 510 E36 2-Me HHH CH2 4-C (Me), CH2〇〇2H 510 E37 2-Me HHH CH2 4-[(1-CH2C〇2H) -cyc- pent-1-yl ] * [M + H] + Unless otherwise indicated Example 7: 3- (4- {5-Chloro-2-oneyl-3- [4- (3-o-o-phenyl-ureido) phenyl] -27 /-Ohridin-1-ylmethyl} phenyl) -propionic acid (E7) The title compound was prepared in a similar manner to that described in Example 1 with the additional step of introducing chlorine. The 3- (4-nitrophenylpyridin-2-one (P3) as N-chlorosuccinimide was similar to I mming et al., Eur Opean J. M ed · C he m. 200] 5 36 (4), 3 75, and 5-chloro-3- (4-nitrophenyl) -1 //-pyridine 44 3) 4938 200409756 ludin-2-i same. An additional modification in the preparation of Bech Example 7 was a nitro group, which was reduced by the method of Production Example 10.

2 //-Pyridin-1-ylfluorenyl} phenyl) -butyric acid methyl ester (0.2 g, 0.4 micromol) was dissolved in tetrahydrofuran (3 mmol solution (0.5 M, 3 ml). Ml) and lithium hydroxide water was added with stirring. Side; the mixture was heated at 6 5 C for 2 hours and then cooled

Instead, it was concentrated under vacuum. The mixture was acidified with hydrochloric acid (2M), extracted with ethyl acetate (2 x 25 liters), and the combined organic layers were washed with brine and then dried over anhydrous sulfuric acid. After filtration, it was evaporated to dryness to give the title compound as a white solid.

(ΊΜ, tj, ^ .14 (2H, s), 3.11 (1H, m), 2.25 (3H, s), 1.18 (3H, d) Examples) 1: [Amidino- (4- {2-one 3--3- (4- (3-o-tolyl_ureido) benzyl] -2 /// "pyridin-1-ylmethylphenyl) amino] acetic acid (El 1) Potassium acid (0.03 5 g, 0.25 mmol) was added to [fluorenyl- (4- {2-S isopropyl-3- [4- (3-o-fluorenyl-phenyl-phenyl) phenyl] -2-A solution of bispyridyl-1, phenylmethyl, phenyl) amino] ethyl acetate (0.90 g, 0.17 mmol) in tetrahydrofuran (5 ml) and at room temperature The mixture was stirred for 2 hours. A solution of sonic acid in diethyl ether (1 M, 1 ml) was added and the solvent was evaporated. The residue was triturated with diethyl ether, filtered and dried to give the title compound as a solid. 45 314938 200409756 1H NMR δ (DMSO-d6): 9.35 (1H, s), 8.10 (1H, s), 7.85 (1H, d) r 7.75 (1H, dd), 7.65 (2H, d) 3 7.55 (1H, dd), 7.47 (2H, d), 7.22 (2H, d), 7.10-7.20 (2H, m), 6.94 (1H, t), 6.61 (2H, d), 6.30 (1H, t), 5.03 (2H, s), 4.06 (2H, s), 2.94 (3H, s), 2.26 (3H, s) compounds [fluorenyl- (4- {2-keto-3- [4- (3-o-tolyl-ureido) Phenyl] -2 D ratio π-determined -1 -ylfluorenyl} -phenyl) amino] ethyl acetate was prepared by the method shown in Reaction Scheme 1. Reaction Scheme 1

/ C〇2Et

Boc

jCT CH3 X02Et Example 23: Octetamidine-3- (4- {2-keto-I [4- (3-o-o-phenyl-ureido) 46 314938 200409756 phenyl] -2U pyridinyl Tian # I 曱 yl} phenyl) propanoic acid (E23) The title compound was prepared using standard procedures described in the text, while the alkylating reagent was similar to 4-bromobenzyl alcohol and 2-fluorenylacetamidomethyl acrylate. The alcohol produced was coupled by the steps of Production Example 4-1. & Example 30 · Fluoro_4_ (3_o-tolyl_ureido) phenyl] _2_g isoyl-2 benzyl group + ylmethyl} _benzyl) propionic acid (E3〇) Preparation system of the title compound According to the methods of Manufacturing Examples 12 and 13 and after preparing Example 7 ~;): the elementary basification step, followed by the hydrolysis of the general method of Example 1. Male, Example 31: (5 > (+ > 3, (4_ {2_keto_3_ [4_ (3_o-tolylureido) phenyl] -2dan-pyridin-1-yl Fluorenyl phenyl) butyric acid (E31) The title compound was prepared from P19 in a similar manner to that in Example 32. [a] D + 14 · 0 (c == 0.5, methanol); MS (ES + ve): [M + H] + at m / z 496 (C3 () H29N3〇4 requires [check mark + at m / z 496). Bayer Example 32: (7〇 +) one 3 one (heart {2__base · 3- [心 (3-O- 曱 phenylphenylureido) phenyl] -2 //-pyridin-1-ylmethylphenylphenyl butyric acid (E32) Lithium hydroxide in water (0.5 M A solution of 40 ml, 20 mmol was added to a solution of P18 (1.02 g, 2.0 mmol) in tetrahydrofuran (40 ml). The mixture was stirred at / m for 3 hours and then concentrated. After adding ethyl acetate, the mixture was acidified by adding 2N hydrochloric acid. The organic phase was washed with water, washed with brine, dehydrated (anhydrous magnesium sulfate) and evaporated. After trituration with diethyl ether, the title compound was obtained as a white solid; [a] D 』C- 14.2. (Cu, methanol); MS (ES + ve): [Μ + ΗΓ at m / z 496 (C3OH29N3 04 requires [M + H], m / z 496). Take the palm ethyl The preparation of the analogue E34 & E35 is similar to the corresponding methyl analogues E3ι and e32 of 314938 47 200409756. The precursor is needed, the heart (Buweikiyl: shouting soil) lower ester, which consists of 4-hydroxy Phenylacetone is prepared according to standard procedures and 4 steps (corresponding to the formation of trifluoromethanesulfonate, carbonylated with palladium acetate under methyl formaldehyde to obtain a fluorenyl ester, and (benzyloxycarbonyl) methyl & 齩= Wittig reaction of the anion of phosphonium ester (Wittig reaction) can not be obtained, this compound can be hydrogenated to obtain the desired saturated acid) Example 3 8: 3-im #

^ (2, keto ~ [[(o- (3-o-phenylphenylurethane) benzyl] _1,2-hydropyridin-3-yl} phenylphenylpropanoic acid (£ 38)

The procedure for preparing the title compound was similar to that described in Example 1 with the intermediate product pyridine, 3 + j-(4-D ratio. 疋 -j-yl-benzyl) ethyl propionate, according to Preparation Example 2 0 and 2 1 method to make ice y ^ is prepared by containing. The subsequent oxidation and recombination into the required pyridones to obtain the square figurine & w, meaning w make the force element basic | The title compound was obtained as a solid by hydrolysis by the method of Example 1. MS (APCI + ve): [M + H] ^ m / z 482 (C29H27N304 f ^ [M + H] ^ at m / z 4 8 2) o Example 39: 3- [4- (3- {4 -Phenyl} _2-keto-2 / 7-pyridine [(l''2,' 3, -a ^ Hydroxy-1-1-ylformamidine [yl] amino] -1 ~ ylmethyl ) Phenyl] propionic acid (E39) 314938 48 200409756

The title compound was prepared from the corresponding ethyl ester (P22) according to the method of Example 1 to obtain the title compound in the solid state. MS (ES + ve): [M + H] + at m / z 494 (C30H27N3O4 requires [M + H] + at m / z 494). Example 40: 3- {4- [2'-keto- 5- (3-o-pyridylphenyl-ureido) -2, //-[2,3,] bipyridyl-1, ylpyridyl > phenylpropanoic acid (E4〇) The title compound is as follows Prepared by the method shown in Reaction Scheme 2. MS (ES + ve): [M + H] + at m / z 483 (C28H26N404 requires [m + H] + at m / z 4 8 3) 〇 49 14938 200409756 Reaction Scheme 2

Method is similar to P8 H2 / Pd / C

ch3

Method similar to P13 HC1 / reflow

v

ch3 1. KOTMS / THF 2. HCi method is similar to Ell

ch3

E40

C〇2H 50 314938 200409756 戸 '' J 41 · ⑺ _ (+) _ 3_ {4υ homo-5 '(3-o- 邻 phenyl-ureido) -2, ugly- [2,3,] bi-D Specific bite ", methylmethyl] _phenyl} sodium butyrate (£ 41)

^ Title compound was prepared from the corresponding methyl ester as a solid compound in a similar manner to that of Example M; [a] d3ctc + 12.5. (C = i 〇, methanol); MS (ES + Ve): [fine] + at m / z 497 (% of C29H needs to be +; + at m / z 497) 〇 Households, plus 42 · (flutter ( -) Winter {4- [2, Keto-5-(3-o-o-pyridinyl phenyl urethane) _ 1 Kai [2,3] bis-pyridin-1-ylmethyl] -phenyl} butanoic acid Sodium salt (E42) A solution of lithium hydroxide in water (0.5M, 5 ml, 2.5 mmol) was added to the corresponding fluorenyl ester (60 mg, 0118 mmol) in tetrahydrofuran (5 ml ) Solution. The mixture was stirred at room temperature for 3 hours. Water (50 ml) and 2M hydrochloric acid (2 ml) were added. Saturated sodium bicarbonate (5 ml) was added to the resulting suspension, and then the solution was allowed to After 10 g of tC18 Se pak ⑧ cartridges (Waters). The column was washed with dilute sodium bicarbonate, then eluted with a water / methanol mixture and evaporated to obtain the title compound as a solid; [α — 12.3. (C = 1_〇, methanol); MS (ES + ve) · [Μ + + Γ at m / z 497 (C29H28N4〇4 requires [] \ 4 +} ^] + at m / z 497). Example 43 : (And) -㈠— {4_ [2_keto_6, _ (3_o- 曱 benzyl-ureido) _ 2 //-[3,3] bipyridin-1-ylfluorenyl] -Benky} Acid hydrochloride (E43) 51 314938 200409756

The compound of Example 43 was prepared by the method of Example 11 to obtain a solid compound.

MS (APCI + ve): [M + H] + at m / z 497 (C29H28N40.4.HC1 requires [M + H] + at m / z 49 7). [a] D29.rc_1 / 10/7. (C = 1 (), methanol). Example 44: (RH〇-3- {4- [2'_ Keto-5- (3-phenyl-ureido [2,3,] bipyridyl-1, ylpyridyl] -phenyl} Butyrate (E44)

The compound of Example 44 was prepared by the method of Example 11 to obtain a solid compound. MS (APCI + ve): [M + H] + at m / z 483 (C28H26N40.4.HC1 requires [M + H] + at m / z 483). [a] d26 6 c] 3_2. (C = 0.5, methanol). Example 45: (R) _ (_) _ 3_ (445- [3- (2-fluorophenyl 1 · ureidob 2 keto-2 //-[2,3,] bipyridyl-1, Amidino} benzyl) butyrate (E45) 314938 200409756

The compound of Example 45 was prepared by the method of Example 11 to obtain a solid compound. MS (APCI + ve): [M + H] + at m / z 50 1 (C28H25FN40.4.HC1 requires [M + H] + at m / z 501). [a] D29 ° C -10.3. (C = 0.5, methanol). Example 46: (±) -3- (3- {2-keto-3- [4- (3-o-pyridylphenyl-ureido) phenyl] hexamuridine } Phenyl) -propionic acid (E46) The title compound was prepared in a similar manner to that described in Example 1 except that the hydrogenation step was carried out under the conditions described in Preparation Example 23. Unless otherwise indicated, the examples listed in Table 2 were prepared in a manner similar to Example 46. The change of the steps is described in Example 50. 314938 200409756

Example R2 LJ Observed * [M + ΗΓ or [M-Η] · or M · E46 Η CH2 3- (CH2) 2 484 [Μ-Η] · Ε47 〇Me CH2 4-iCH?)? 516 Ε48 Η CH2 ^ (CH7) 7 486 Ε49 〇Me CH2 (± > 4-CH (Me) CH2 530 Ε50) bond 4- (CH?) 7 472 Ε51 〇Me bond 4- (CH?)? 502 [M + H) + unless otherwise specified

Example 50: 3- (4- {2-keto-3- [4- (3-o-tolyl-ureido) phenyl] hexahydropyridine-1 -yl} phenyl) propionic acid (E 5 0) The title compound was prepared from 3- {4- [3- (4-nitrophenyl) -2-S isopropyl-2 //-D than hydradin-1-yl] benzyl} propion prepared in Preparation Example 24 Ethyl acetate and the latter are individually prepared similarly to the steps of hydrogenation, urea formation, and hydrolysis of Production Example 23, Production Example 9 and Example 1. 54 314938

Claims (1)

JU's patent application scope: 1. A compound of formula (I) or an A /, W acceptable derivative: A and B are independently aryl or heteroaryl. Together form 5 to Q is C, CH or a ring with the group v or the group l'D; D is hydrogen 'C " alkyl or forms a 5 to 7-membered heterocycle with the group Q_ R], R2 and R3 are independently c [Chen], [Chen], -6 alkyl, halogen, 1-6 alkoxy, fluorenyl, cyano, cf3, nitro, c] 6 alkylthio, amine, mono- or di-CK6 alkylamino, Carboxyl, C] · 6 醯, 醯 amino, mono- or dialkyl —amino, NHCOR9 or NHS〇2R9 where R9 is c "alkyl", 6 C3 · 7 cycloalkynyl or this group (up to as needed Three groups selected from c] 6 are substituted by a group consisting of prime, c] _0 alkoxy, cyano, phenyl or CF3) or a group l (CH2)] _ 6NRT where E is a single bond or- 〇CH2i Rx and two are independently hydrogen, C! _6 alkyl or together to form a 5- to 7-membered heterocyclic ring; R is hydrogen 'cN6: i: endyl' halogen or c ^ 6: j: endoxyl; v 0, S, NH, N-Cu alkyl, NNO2, NCN or with group Q 314938 55 200409756 together to form a 5 to 7-membered heterocyclic ring;, Y, Z are independently c, CH or CH ............ single bond or double Bond; L is-(CH2) q- or-(CH2) q'〇- where q is 〇 is 2 or 3; ⑴-CR5 = CR6- where R5 and R6 are independently hydrogen or c] (ii) -CHRLCHRL where r7 and R8 are independently hydrogen, 'C3_7 cycloalkyl, aryl, heteroaryl, -Nhcor9- or wherein R9 is as defined above or CH2) I-6NRxRy where 1 is as defined above; or (iii) a single bond; or (iv)-CHR6- where R6 is as defined above; or (v) -0-CHR]. -, _Nru_chr] 〇- or -CR] 2r13_chr and R]] are independently hydrogen or C]. 6 alkyl groups are combined with R "and R] C] 6 alkyl groups or R " and R! 3 to form Ch 5 to 7-membered heterocyclic ring; m, n and p are independently 0, 1, 2 or 3; and t is 0, 1 or 2. 2. The compound as claimed in claim 1 of the patent scope, wherein a σ 3. If the compound of the scope of application for patent 1 or 2 is phenyl, 4. For the scope of application of patent 4] for any one of the items] to 3: or 3 and q, -6 alkyl; Or Cl-6 alkynyl, Rx and Ry 1G in -NHS02R9 ^ -here R1. ° is independently 7 cycloalkyl or | phenyl or pyryl, where B is a compound of which 56] 314938, R], R2 and R: 3 is independently Ci · 6 alkyl, halogen, C] (; alkoxy, tris, cyano, CF3, nitro, ct K6 thio, amine, mono- or di-C 6 Amine, carboxyl, Cl-6 alkylamido, amido, mono- or di-C6 alkylamido'NHCOR9 or RSO2R9 where R9 is c alkyl, Cy cycloalkyl or benzene (If necessary, select up to three) · υ from C] 6-Alkyl 'halogen, C 1 -6-oxyl, cyano, this Group, or CF3 i-group substitution) or -E- (CH 2)]-6NRxRy where e is a single bond or -och2- and Rx and R.y are independently hydrogen, Ci_6 alkyl groups or together form Includes hexahydro D ratio σ amidyl 'hexahydrocarbyl group, D ratio α each. The ring of definite group or morpholinyl in which the ring is optionally substituted with 1 C]-6 alkyl group; formed when Q and V combine Including hexahydropyridyl, hexahydropyridyl, and slightly bitten: When it is a phenyl or morpholinyl ring, it can be optionally substituted with C] -6 alkyl; Quoda Q combines with D to form Hydropyridyl, hexahydropyridinyl 'Q than pyridinyl: When it is a cyclinyl or morpholinyl ring, it may be optionally substituted with C] · 6 fluorenyl groups; 200409756 is (i) -CR5 = CR6-here R5 and R6 are independently hydrogen or Ch alkyl; (ii) a CHR'CHR8-here R7 and R8 are independently nitrogen, c] (alkyl, Cs · 7 cycloalkyl, phenyl, naphthyl, thiophene Base, haloyl, 17-base, trisyl, trisyl, trisyl, thiazolyl, thiazolyl, isothiazolyl, isothiazolyl, thiazolyl, thiadiazolyl, Pyrazolyl , Pyrimidinyl, daphnyl, glutinyl, pyridyl, quinolinyl, isoquinolyl, π-injection |] dolyl 5 314938 57 200409756 pyrene, benzofuranyl, benzothienyl, benzimidazole Group, benzoyl group, -NHCOR, or _NHs〇2r9_ where r9 is as defined above or-(CH2)]-6NRXRy where nrx & rv is as defined above; or (iii) a single bond; or (iv) -CHR Here, R6 is as defined above; or (v)-OCHR] 0-, -NR-CHR], or -CR] 2Ri3-CHRl0_ here stands for hydrogen or u group and R and R are independently C]. 6 alkyl or r12 & r] is combined to form c3 7 cycloalkyl hexahydropyridyl, hexahydropyridyl, group; contains%, and, y and 2; the ring is' tetrahydropyranyl, Mouth ratio ° each. Morpholine or morpholine The compound of item 4, its 4 element or alkoxy group is any one of item 1 to item 4 in the patent application scope, R], R2 and R. Is independently a C] 6 alkyl group, the group Q 'is C, CH or a moiety with V or -azole or an indole ring; D is hydrogen, c] -6 alkyl or a moiety with an oxazole ring; D The groups together form a benzimidazole. The Q groups together form a benzimidazole, benzo ° or benzo 3) 4938 58 200409756 V is ◦ or together with the Q group R4 is hydrogen or halogen; · Part J is ⑴ C] -CR5 = CR6- where R5 and R6 are independently hydrogen or radical; or (Π) -CHR7-CHR8-where R7 and R8 are independently hydrogen, c] · 6 radical, c3_7 cycloalkyl, phenyl, -NHCOR9- where R9 is c alkyl; or (iii) a single bond; or (iv) -CHR6- where R6 is as defined above; or (v) -〇-CHR10-, _NR ]] _ CHR] 0- or _CRI2R] 3-CHR10- where R] G and R]] are independently hydrogen or Cw alkyl and R] 2 R〗 3 are independently CV6 alkyl or R] 2 and R] 3 together to form C3_7 cycloalkyl. 6. The compound according to item 1 of the scope of patent application, wherein the compound is (la) or a pharmaceutically acceptable derivative thereof. Alkanes 1 -6 (la) 59 3) 4938 200409756 R'R2'V'R4, L, J, m, η, p, and t are defined as shown in formula ⑴. For example, the compound in any one of the first to sixth items of the patent application range, wherein R1, R2, and R3 are independently C] _6 alkyl, functional element, c] _6 alkoxy, aryldiyl, cyano, CF 3 ,; & Shaw, c] _6-sulfanyl, amine, mono- or one-to-one C] · 6 alkylamino, carboxyl, (:) · 6 alkylfluorenyl, fluorenylamino, mono · Or dialkylammonium, NHCOR9 or NHS〇2R9 where R9 is Ci 6 alkyl, 6 C 3-7 cycloalkyl or as many as three via C] -6 alkyl, halogen, c] oxy , Cyano, phenyl or CFs substituted phenyl; L is-(CH2) q where q is 0, ι, 2 or 3; and J is ⑴-CR5 = CR6- where R5 and R6 are independently hydrogen Or Gw alkyl; or (11) -CHR7-CHR8- Here R7 and R8 are independently hydrogen, 6 less complete, -NHCOR9- or NHS〇2R9, where R9 is defined as the first item in the scope of patent application. 8. The compound according to any one of claims 1 to 7 in the scope of patent application, wherein J is -CH = CH-,-(CH2) 2 -'_ CHR7-CH2-, where R7 is a C alkyl group. K6 9. The compound according to item 1 of the scope of patent application, which is selected from the group consisting of El to E5] or a pharmaceutically acceptable derivative thereof. 10. The compound according to item 1 of the scope of patent application, which is selected from the group consisting of E5, E9, E ^ 2, E4I, E42 and E51 or a pharmaceutically acceptable derivative thereof. 11. A method for preparing a compound of formula (I), comprising hydrolyzing a carboxylic acid ester derivative of formula (Π): 60 314938 200409756 D Here R] to R4, m, η, p, t, A, B, D, L, J, Q, V, W, X, Y, and Z are defined as in formula (I), and R is capable of forming a carboxyl group. Acid esters and, if necessary, groups which form their pharmaceutically acceptable derivatives. 12. A compound according to any one of claims 1 to 10 of the scope of patent application, which is used for treatment. 1 3. A pharmaceutical composition comprising a therapeutically effective amount of a compound or a pharmaceutically acceptable salt of any one of claims 1 to 10 and a pharmaceutically acceptable carrier or diluent. 1 4. A pharmaceutical composition comprising the compound according to any one of claims 1 to 10 or a pharmaceutically acceptable derivative thereof and another therapeutically active agent. 1 5. —The use of a compound according to any one of claims 1 to 10 in the scope of patent application, which is used to manufacture a disease for treating or preventing an inhibitor beneficial to the cell adhesion regulated by 4 Medicine. 16. A method for treating or preventing a condition in which an inhibitor is beneficial to α 4-regulated cell adhesion, which comprises administering a safe and effective amount to a patient in need thereof, such as in the scope of the patent application] item 1 to 1 Compound of any one of 0 items. 5] 4938 200409756 1 7. If the scope of the patent application is for stem rheumatoid arthritis II: the disease system is selected by 1 group; Amm / ,: adult respiratory distress syndrome ... Azmer disease; cardiovascular disease; thrombosis A is also known Blood stalks, words 隹 · / 彳 板 彳 π, thrombus dissolve and then occlude; report; skin inflammatory diseases; diabetes; multiple sclerosis; whole body 2: lupus; inflammatory bowel disease; Guan ' Diseases; related to Lymphocydia 7, called the door to the month, the lymphoid infiltration to the epithelial linear group inflammation; mastitis; liver diseases _ ο κ disease 'pancreatic machinery γ person, bile Xianghuo, cholangitis or bile duct Zhou Yan. Detubitis; Rhinitis; Pulmonary Inflammatory Disease; Collagen Disease II-Branches-Guang Guang Guan ... Arteriosclerosis; Neoplastic Disease; Trauma., Disease; Sjgren Syndrome (sjGgren, ssyndrGme = Rejection after private implantation; host-to-graft or graft-to-host ° .s Endothelial hyperplasia; Arteriosclerosis; Post-operative inflammation; Tumor angiogenesis; Malignant tumors; Multiple stenosis again; Kidney-induced bone Reabsorption · Major tumors and myeloma's disease (Meniere, sd ... Positive: ®Nervous System Injury and Menier Burn UVieniere s dlsease). 18 · If the method of the 16th area of the patent application, $ Allergic conditions, inflammatory bowel disease /; Asthma, asthma, skin fire, multiple sclerosis or rejection after organ transplantation. &Quot; Sex3] ^ 938 62 200409756 指定, designated representative: No scheme in this case ( A) The designated representative of the case is: . () In FIG. (B) element symbol representing a representative diagram of the present briefly described: 捌 If there is a chemical formula in this case, please disclose the chemical formula that can best show the characteristics of the invention: 4 3] 4938